Estrogen receptor (ER)-positive breast tumors are treated with endocrine therapies which specifically target the ER. Patients can remain disease-free for many years; however, resistance to treatment eventually develops, and the majority of women will suffer a recurrence of metastatic cancer. We hypothesized that the key to the long-term treatment of women with ER-positive breast cancers was to focus on identifying novel mechanisms of resistance using metastatic tumors resistant to therapy where tumor evolution and clonal selection have occurred. We identified the androgen receptor (AR) as a new clinical target which was up regulated in resistant, metastatic tumors. We have learned that AR functionally collaborates with ER, and that resistance may be associated with a failure of hormone therapy to completely block both androgen and estrogen signaling. We have also discovered that AR-overexpressing cells become metastatic in vivo. Furthermore, we were the first to identify that the estrogen receptor ESR1 gene can be mutated in metastatic tumors; acquiring hormone-independent and endocrine therapy-resistant functions which we hypothesize will also be impacted by ligand-independent AR signaling. Importantly, cells with ESR1 mutations also up-regulate AR, demonstrating a unique relationship between these mutations and AR. Our Aims are: (1) To determine if receptor crosstalk (WT or mutant ER with AR) is a mechanism of resistance to hormonal agents, (2) To determine whether AR employs novel nuclear receptor interactions to drive hormone resistance, and (3) To determine AR and ESR1 mutant effects on invasion and metastasis. Key success has been made in developing resistant models with endogenous up regulation of AR coincident with acquired resistance, and we have already identified potential AR-mediated candidate resistance mechanisms. Undoubtedly hormone therapy resistance in patients is multifactorial and will require combination hormonal and targeted therapy along with knowledge of the activation status of key pathways, such as those arising from mutations in ER in metastatic tumors. Our work will impact a large number of women with ER-positive breast cancer who recur with therapy-resistant disease.